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DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer

Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell gro...

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Autores principales: Bévant, Kevin, Desoteux, Matthis, Abdel Wahab, Abdel Hady A., Abdel Wahab, Sabrin A., Metwally, Ayman Mohamed, Coulouarn, Cédric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468746/
https://www.ncbi.nlm.nih.gov/pubmed/34571856
http://dx.doi.org/10.3390/cells10092207
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author Bévant, Kevin
Desoteux, Matthis
Abdel Wahab, Abdel Hady A.
Abdel Wahab, Sabrin A.
Metwally, Ayman Mohamed
Coulouarn, Cédric
author_facet Bévant, Kevin
Desoteux, Matthis
Abdel Wahab, Abdel Hady A.
Abdel Wahab, Sabrin A.
Metwally, Ayman Mohamed
Coulouarn, Cédric
author_sort Bévant, Kevin
collection PubMed
description Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGFβ pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways.
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spelling pubmed-84687462021-09-27 DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer Bévant, Kevin Desoteux, Matthis Abdel Wahab, Abdel Hady A. Abdel Wahab, Sabrin A. Metwally, Ayman Mohamed Coulouarn, Cédric Cells Article Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGFβ pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways. MDPI 2021-08-26 /pmc/articles/PMC8468746/ /pubmed/34571856 http://dx.doi.org/10.3390/cells10092207 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bévant, Kevin
Desoteux, Matthis
Abdel Wahab, Abdel Hady A.
Abdel Wahab, Sabrin A.
Metwally, Ayman Mohamed
Coulouarn, Cédric
DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer
title DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer
title_full DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer
title_fullStr DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer
title_full_unstemmed DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer
title_short DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer
title_sort dna methylation of tgfβ target genes: epigenetic control of tgfβ functional duality in liver cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468746/
https://www.ncbi.nlm.nih.gov/pubmed/34571856
http://dx.doi.org/10.3390/cells10092207
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